Method for diagnosing and alleviating the symptoms of chronic fatigue syndrome

ABSTRACT

A method for alleviating chronic fatigue syndrome with the administration of antiviral agents. Based on clinical tests, chronic fatigue syndrome is a persistent herpes virus infection and thus administration of antiviral agents are shown to alleviate the symptoms associated with the disorder. Based on therapeutic trials, patients receiving the recommended antiviral treatment, have experienced significant reduction or elimination of the symptoms associated with chronic fatigue syndrome. A method of diagnosis of the chronic fatigue syndrome is further disclosed.

TECHNICAL FIELD

This invention relates to a method of alleviating the symptomsassociated with chronic fatigue syndrome through the use of antiviralagents.

BACKGROUND ART

Chronic fatigue syndrome (CFS) is a disorder which, until recently, hadno formalized name, received little attention and was believed by themajority of the medical community to be a psychological rather thanmedical disorder. However, as information about the disorder has beendisseminated, the symptoms associated with the disorder, as well as thegrowing number of people afflicted with this disorder, have steadilyincreased to alarming proportions. In fact, CFS is being reported withincreasing frequency throughout the world.

Chronic fatigue syndrome is a puzzling, exasperating illness wherebypreviously healthy, vigorous and productive young or middle-aged adultsare suddenly afflicted with a persistent, overwhelming fatigue. Whensuch a severe debilitating fatigue extends beyond six months andpsychiatric disease is excluded, the condition has been termed "chronicfatigue syndrome." Despite the number of people afflicted with chronicfatigue syndrome and the recent research attention, to date, the causeof the disorder remains unknown.

The medical community has only recently defined the term "chronicfatigue syndrome" to have a distinct and well-defined meaning. In theJournal of the Royal Society of Medicine, Vol. 84, February, 1991,chronic fatigue syndrome is defined as:

"A fatigue which is the principal symptom, which has a definite onset,and is severe, disabling and affects both physical and mentalfunctioning, and furthermore that fatigue should have been present for aminimum of six months at which it was present for more than 50% of thetime."

One or more of the following symptoms are generally associated with thesyndrome, such as sleep disturbances (changes in the duration of sleepand/or quality of sleep), impairments in concentration and short-termmemory, chronic and recurrent low-grade fever, and musculoskeletal pain.The changes in the duration of sleep could be hypersomnia or increasedsleep, or insomnia or reduced sleep. The changes of the quality of sleepare contemplated to be due to a decrease of REM sleep. There is alsogenerally a restriction or lack of ability to perform an activity in themanner or within the range considered normal for a healthy human being,(resulting from loss of psychological or physiological function). Thereis further a definite persistent change from a previous level offunctioning.

Mood disturbances such as depressed mood, and anhedonia, anxious mood,emotional lability, irritability, and severity of the mood disturbancesshould be assessed on standards scales. For diagnosis purposes, apatient's symptoms should be evaluated to determine whether suchsymptoms are attributed by a psychological condition, such as adepressive disorder rather than chronic fatigue syndrome. It should thusbe determined whether the disorder is sufficient to meet the diagnosticcriteria for major depressive disorders. In CFS patients, myalgia, whichis pain or aching felt in the muscles, should be disproportionate toexertion. Such myalgia should be distinguished from feelings of weaknessand pain felt in other areas such as the joints. Certain patients shouldbe excluded from the definition of CFS, such as patients withestablished medical conditions known to produce chronic fatigue such assevere anemia. Additionally, patients with schizophrenia, manicdepressive illness, substance abuse, eating disorders, or proven organicbrain disease should be excluded as chronic fatigue syndrome sufferers.However, other generalized psychiatric disorders may be attributed tochronic fatigue syndrome.

A variety of treatments have been suggested and utilized for thetreatment of chronic fatigue syndrome. In U.S. Pat. No. 5,312,817, thereis described a treatment of the chronic fatigue syndrome wherein apharmaceutically-acceptable cholinesterase inhibitor or a prodrugtherefore is administered for the treatment of fatigue syndromes. Thistreatment is based on the understanding that the mechanism of thefatigue could be an imbalance in the cholinergic nicotinic transmittersystem, both peripherally and centrally, which decreases theacetylcholine in the central and peripheral synapses. However, thistherapy has proven ineffective, as this mechanism does not properlydescribe the etiology of chronic fatigue syndrome.

In a further example, U.S. Pat. No. 5,055,296 discloses a treatmentinvolving the administration of mammalian liver extract. Yet anotherexample is provided in U.S. Patent No. 5,013,739, whereby an opiatereceptor antagonist is administered as a treatment option. In addition,a variety of drugs have been prescribed for symptomatic relief includingnon-steroidal anti-inflammatory drugs, tricyclic anti-depressants,sleep-inducing drugs, tranquilizers, anti-anxiety and stress-relievingdrugs such as androstenediol and androstenetriol. Such symptomatictreatment efforts, while providing temporary relief for one of theassociated symptoms, have in general provided no long-term treatment ofthe disorder as a whole.

In addition to the physical pain associated with this disorder, there isalso a severe mental and emotional toll placed on the CFS sufferer. As aresult of the prolonged and debilitating fatigue, and flu-like symptoms,CFS sufferers are forced to reduce their level of activity, and areoften unable to lead what would be considered a normal life.

Accordingly, there is a genuine need for a method of treating chronicfatigue syndrome with a reliable, and effective technique which allows aCFS sufferer to regain a normal level of activity without the associatedpersistent fatigue characterized by the disorder.

SUMMARY OF THE INVENTION

It would be desirable to provide a method for alleviating the symptomsassociated with chronic fatigue syndrome by administering antiviralagents to target the cause of the disorder. It would further bedesirable to provide a treatment for chronic fatigue syndrome throughadministration of an antiviral drug which is directed to the cause ofchronic fatigue syndrome rather than one that addresses a particularcondition or symptom. It would be yet further desirable to provide along-term treatment approach whereby chronic fatigue sufferers couldresume a normal level of activity without experiencing extreme fatigue.

In carrying out the above objects, a method is disclosed for alleviatingthe symptoms of chronic fatigue syndrome, including administering to apatient in need thereof, a therapeutically effective amount of one ormore pharmaceutically acceptable antiviral agents, wherein the one ormore antiviral agents are selected from the group consisting ofacyclovir, ganciclovir, valacyclovir, famciclovir, cidofovir, andpharmaceutically acceptable derivatives and mixtures thereof.

There is further disclosed a method of diagnosing chronic fatiguesyndrome (CFS) in a patient, including the steps of: evaluating thepatient for serologic evidence of Epstein-Barr virus (EBV) and humancytomegalovirus (HCMV) infection; and monitoring the patient for T-waveabnormalities by 24-hour electrocardiographic (Holter) monitoring todocument the persistent cardiac pathology which is the basis of the CFS.The serologic evidence of EBV and HCMV is obtained by studying the levelof antibodies of EBV and HCMV to detect the presence of active andpersistent multiplication of either or both of the viruses. Inconjunction therewith, tests are conducted to verify the existence of acardiomyopathy in the CFS patient. Based on the results of the tests andthe determination of the cause of CFS, the patient is administered aspecific antiviral agent suitable for EBV, HCMV or the combination.Following initial antiviral treatment, supplemental tests are conductedto check for recurrent CFS to determine an appropriate treatment periodfor the patient to achieve continued alleviation of the CFS symptoms.

The above objects and other objects, features, and advantages of thepresent invention are readily apparent from the following detaileddescription of the best mode for carrying out the invention.

DETAILED DESCRIPTION OF THE INVENTION

As defined herein, a "therapeutically effective" amount of an antiviralagent is the amount by which a patient's chronic fatigue syndromesymptoms, such as severe fatigue, headaches, sore throats and the like,decrease in frequency and/or intensity. In addition, the term"alleviating" as used throughout the specification refers to relievingor reducing symptoms associated with chronic fatigue syndrome and/orelimination of those symptoms.

Likewise, the term "pharmaceutically acceptable antiviral agent" isdefined to include those antiviral agents which, upon administration,have no deleterious effect on the patient. Thus, where a particularantiviral agent is unsuitable for a particular individual, thatantiviral agent would not be pharmaceutically acceptable and would thusnot be administered.

In general, the clinical symptoms and signs of chronic fatigue syndromeresemble those of infectious mononucleosis. Symptoms common to bothillnesses include low-grade fevers, chills, sore throats, painfulanterior or posterior cervical or axillary lymph nodes, muscle weakness,myalgias, generalized headaches, migratory arthralgias, vagueneuropsychological complaints and disturbances of sleep without knownmedical cause. As with mononucleosis, a CFS patient's attempt toexercise at levels previously tolerable, results in a prolonged and moresevere manifestation of the fatigue.

While CFS and infectious mononucleosis have several similarities,patients with CFS do not have the severe dysphagia and gray exudativepharyngitis often accompanied by submandibular adenopathy, associatedwith infectious mononucleosis and its etiologic agent Epstein-Barr virus(EBV). Our research has found in CFS sufferers the existence ofEpstein-Barr virus multiplication, purportedly within epithelial cellsof the pharynx and circulating B-lymphocytes of the blood. The betaherpes virus, human cytomegalovirus (HCMV) is also believed to causeinfectious mononucleosis-type symptoms, without the exudativepharyngitis. Mononucleosis and chronic fatigue syndrome thus havecertain similar symptoms.

Specific emphasis must however be placed on symptoms unique to chronicfatigue syndrome. Such symptoms include: 1) light-headedness orwooziness of varying severity and duration without known antecedentcause; 2) a vague, dull, pressure-like chest ache, generally in thesubsternal region and sometimes including the left shoulder, which isexhibited with increasing fatigue at the end of the day; and 3)palpitations. There is also often a fourth symptom, tachycardia or rapidheart action, even with minimal or no exertion by the sufferer. Based onthe symptoms unique to chronic fatigue syndrome, it is furtherhypothesized, that chronic fatigue syndrome is essentially cardiac inorigin, and that this cardiac basis unlocks the key to the disorder.

Accordingly, while not wishing to be bound to any particular theory, itis believed that the majority of cases of chronic fatigue syndromeconstitute either a continuing primary herpes virus infection,specifically Epstein-Barr virus and/or human cytomegalovirus, oralternatively, a reactivation infection with latent Epstein-Barr virusand/or latent human cytomegalovirus. In some lesser number of cases,herpes virus 6 (HHV-6), or other viruses, such as enteroviruses may beinvolved. Seroepidemiologic studies indicated the presence of EBV and/orHCMV in CFS sufferers. Our research has further indicated for CFSsufferers the existence of IgM antibodies to the EBV viral capsidantigen (VCA) or EBV antibodies to early antigen (EA), the latterdepicting EBV DNA polymerase activity, indicating current virusmultiplication. In CFS sufferers, there may additionally oralternatively be a significant IgG enzyme immunoreactive antibody(ELISA) to HCMV, with/without an IgM (ELISA) antibody titer to HCMV.

The understood virologic cause of CFS thus verifies that previousseroepidemiologic studies attempting to show a singular virologiccausation to CFS including singular searches for EBV or HCMV antibodieswould have naturally yielded uniformly negative results. At leastfifteen different viruses, bacteria and parasites have been previouslysuspected as "singular" etiologic agents of CFS. However, there hasbeen, to date, no serologic association with any human virus. It isbelieved that the previous studies were designed in a way that actuallymasked the possibility of finding a major two-virus causality.

The two proposed major causative herpes viruses, EBV and HCMV, arecharacterized by latent, non-permissive, persistent infections. In anon-permissive infection, a complete infectious virus is not produced.Intracellular infection produces a metabolically altered host cell,however, no progeny capable of infecting a new susceptible cell arecreated. Instead, the extra-chromosomal herpes virus episome persistsfor the life of the chronically infected cell. The latent, persistentinfection and recrudescent infection characteristic of the herpes virusis common in EBV and HCMV and is consistent with the chronicrecrudescent illness of CFS.

Productive whole-virus, herpes virus, EBV, or HCMV infection isaccompanied by lysis of infected cells. In latent infection, completeinfectious virus is not produced, and host cell survival continues. Withpersistent infection, varying levels of infectious virus, latent virus,and reactivation may occur simultaneously. Productive infection is alsoassociated with cellular necrosis and a subsequent inflammatoryresponse. Latency may be associated with little inflammation ormorphological changes, but may lead to only biochemical aberration anddegenerative cellular functions.

There is evidence that supports the theory that both HCMV and EBV arecardiotropic for the human myocyte. Based on our research, it isbelieved that the human cardiac myofiber, like the B-lymphocyte for EBVand the mononuclear progenitor cell for HCMV, is a site ofnon-infectious episome-mediated persistent infection. This is differentfrom the human epithelial cell of the pharynx which produces mainlywhole infectious EBV virus. HCMV immediate-early gene transcripts havebeen detected in the heart by in-situ hybridization techniques inpatients with HIV-associated cardiomyopathy. Likewise, the EBV genomewas detected by polymerase chain reaction amplification of DNA extractedfrom the heart at autopsy. However, polymerase chain reaction (PCR) forenteroviruses and cardiac viral cultures were negative. An intensemononuclear cell infiltrate in the myocardium consisted essentially ofT-cells without identifiable B-cells.

Accordingly, our research has indicated that CFS is a non-permissive,persistent herpes virus infection of the heart, wherein EBV and/or HCMVnucleic acids are present in the hearts of CFS patients. This hypothesiswas generated based in part upon endomyocardial biopsies of patientswith CFS.

The research conducted revealed that all CFS patients have abnormaloscillating T-wave flattenings and T-wave inversions detectable from24-hour electrocardiographic (Holter) monitoring. An initial 24-hourelectrocardiographic T-wave study compared CFS patients to randomnon-CFS patients, from an internal medicine practice, wherein bothpatient groups were restricted to an age less than 50 years old tominimize the occurrence of chronic diseases in both populations.Notably, chronic diseases such as hypertensive vascular disease,electrolyte abnormalities and coronary artery disease may producesimilar oscillating abnormal T-waves. However, since people sufferingfrom CFS are generally young, such chronic diseases rarely afflict CFSsufferers and can thus be excluded as the causative agent. OscillatingT-wave abnormalities described also occur in about 5% of normal patientswhen they assume an upright position. For these same patients, restingtwelve-lead standard ECG, T-waves describing left ventricular electricaldepolarization are upright, and the resultant ECG is normal. The 2-Dechocardiogram also generally is normal, however, the 24-Hr. ECGrecordings (Holter monitoring) are abnormal with oscillating T-waveflattenings or T-wave inversions characteristically incident with theonset of sinus tachycardias, and subsequently, reverting to normalT-wave configurations with the return of normal sinus rhythms. Whilethese abnormal T-waves are not specific to CFS, they occur similarlywith diverse conditions such as coronary artery disease, hypertensivevascular disease and electrolyte abnormalities, but the abnormal T-wavesdetected via Holter monitoring were seen much more frequently in 24random CFS patients than 116 time, place and age-matched random non-CFSpatients. Based on our analysis, the abnormal T-waves at 24-Hr. ECGrecordings in CFS patients are not "artifacts", and are a significantsign of CFS. The abnormal Holter monitoring in CFS patients is evidencethat CFS is a cardiomyopathy. Moreover, we have found that theadditional symptoms of a dull chest ache coming on at the end of the daynot related to exercise, light-headedness or wooziness and palpitationsare CFS symptoms attributable to cardiac involvement by these viruses.

Holter monitoring is further utilized and discussed in more detail inU.S. Pat. No. 5,454,020 issued to A. Lerner on Nov. 7, 1995; U.S. Pat.No. 5,357,968 issued to A. Lerner on Oct. 25, 1995; and U.S. Pat. No.5,213,106 issued to A. Lerner on May 25, 1993.

An initial group of CFS patients, additionally, demonstrated abnormalleft ventricular dynamics characterized by a decreased or fallingejection fraction, abnormal wall motion or dilatation by radionuclidestress multiple gaited acquisition (MUGA) studies. Furthermore,consecutive case series of CFS patients from a single referral center atBirmingham, Mich. during the years 1987-1993 demonstrated abnormal leftventricular dynamic function in 24.1% of 87 patients undergoingradionuclide ventriculography by the radioisotopic gaited pool method.

In an effort to diagnose CFS, using electron microscopy, cardiomyopathicchanges including myofiber hypertrophy, myofiber disarray anddegenerative change in myofibers have been seen. On rare occasions,inflammatory myocarditis is evident. Infectious HCMV is not found in theheart, peripheral blood or urine of this HCMV-CFS subset of patients.Based on the evidence gathered, it is believed conclusively that CFS isa major newly discovered cardiomyopathy.

On the basis of this research, chronic fatigue syndrome is understoodfurther to be a persistent, non-permissive herpes virus infection of theheart. CFS patients have abnormal Holter monitoring reflecting thatcardiomyopathy. Additionally, the majority of CFS patients have theappropriate serologic markers of persistent EBV and/or HCMV infections.Research has led to the understanding that HCMV and/or EBV nucleic acidsare present in myofibers (myocytes) of cardiac tissues of the CFSpatients which are detectible by polymerase chain reaction (PCR) orin-situ hybridization techniques. Additionally, it is believed that EBVand/or HCMV nucleic acids will not be present in the myofibers of EBV orHCMV serologically positive, non-CFS patients undergoing similar cardiacbiopsies. We have further observed that patients with acute primary EBVinfectious mononucleosis who recover rapidly have normal Holtermonitoring throughout their illnesses. It is thus believed that theseEBV-infected patients have no cardiomyopathies. On the contrary,patients with prolonged illnesses of acute primary EBV-infectiousmononucleosis exhibit abnormal Holter monitoring which substantiates ourunderstanding of the mechanism of CFS.

Given the pathologic physiology of herpes virus infections in humans,the etiologic diagnosis resulting from this research is notcontradictory. Just like CFS, herpes simplex virus encephalitis (HSVE)boggled the medical community and etiologic identification due to therising antibodies in serum which may or may not be present at a giventime. Diagnosis of HSVE required isolation of herpes simplex virus, Type1 from the brains of patients with encephalitis.

Rowe, Bou-Halaigah, Kan and Calkins recently reported that CFS patientsexhibited an abnormal blood pressure response in an upright tiltposition. The Relationship Between Neurally Mediated Hypotension and theChronic Fatigue Syndrome, JAMA, 1995; 274: 961-967. This abnormalresponse was explained to be the result of an abnormal neural reflexcaused by CFS. Our research disproves this theory, rather CFS is acardiomyopathy inducing the reported abnormal cardiac response, which isfurther supported by the abnormal T-wave findings at Holter monitoringwe have discovered.

Having tracked the etiologic agents of CFS, an intense study of EBV andHCMV followed. Epstein-Barr virus infection starts in the oropharyngealepithelium. The cells in this region are permissive for virusreplication and thus a persistent active lytic infection continues inthis region for many years. It is believed that in the primary infectionlevel, Epstein-Barr virus infects B lymphocytes. Similarly, the cellularsites for latency for HCMV are the mononuclear phagocyte and itsprogenitor cells. In the case of HCMV, when the monocyte differentiatesinto the macrophage or histiocyte, infectious HCMV virus productionensues with an associated irreversible destruction of the infected cell.

Epstein-Barr virus is the prototype for the lymphocryptovirus genus. Thelymphocryptovirus is a closely related member of the gamma herpes virusfamily. The host range of these viruses in-vitro is restricted toprimary lymphocytes of the immunoglobulin-producing lineage(B-lymphocytes). The lymphocytes are also a site of latent virusinfection in-vivo. In-vivo, most human EBV infection starts in theoropharyngeal epithelium. Epithelium cells allow herpes virusreplication and thus a persistent, active lytic infection continues formany years. During the course of primary infection, EBV infects Blymphocytes. EBV does not usually replicate in B lymphocytes but insteadestablishes latent infection. Early in human infection, EBV-infected Blymphocytes can be found in large numbers in peripheral blood andtissues.

Much evidence supports the understanding that lymphocytes or similarcell type are the major site of latent infection for EBV and areimportant in the dissemination of infection to distal epithelialsurfaces or in continuously reactivating the oropharyngeal epithelium.The EBV infection generally follows a specific pattern of events. In afirst instance, the virus initiates infection of the oropharyngealepithelium, where it can produce symptomatic pharyngitis. B-lymphocytesare then infected as they reside in close proximity to the oropharyngealepithelium. The lymphocytes then carry the virus to other organs and toepithelial surfaces, including the oropharynx. Furthermore, persistentreplication in the oropharynx is likely dependent on lymphocytereinfection of oropharyngeal epithelial cells. After the primary EBVinfection, the emergence of Burkitt's lymphoma, Hodgkin's disease, andnasopharyngeal carcinoma is believed to be linked to EBV.

Most human peripheral blood B lymphocytes are susceptible to EBVinfection. The cells become latently infected and are driven toproliferate by the latent virus genome. People infected with EBV have Blymphocytes in the peripheral blood which are able to proliferate intolong-term lymphoblastoid cell lines in vitro. All cell lines that growout of the peripheral blood of normal humans are EBV-infected Blymphocytes. Thus, EBV provides B cells with the ability to multiplyindefinitely.

The persistence of EBV in human populations appears to be dependent onoropharyngeal multiplication of virus, and salivary spread to theoropharynx of uninfected humans. Most disease manifestations are relatedto lytic infection in oropharyngeal epithelial cells, to latent virusinfection in tonsillar or peripheral blood B lymphocytes or to immuneresponses to virus-infected cells.

Human cytomegalovirus (HCMV) like all of the herpes viruses, has incommon certain distinguishing features, including virion and genomestructure and the ability to establish persistent and latent infections.In addition to these common herpes virus features, HCMV has certaindistinct characteristics, such as salivary gland tropism, speciesspecificity and slow growth in cultured cells. HCMV infects 50% to 80%of the population. HCMV can be structurally distinguished from otherherpes viruses by subtle ultrastructural differences in the virionappearance, for example, the HCMV envelope generally appears morepleomorphic in relation to other herpes viruses. HCMV generally producescell enlargement with intranuclear inclusions similar to those producedby herpes simplex and varicella zoster virus. The sources of HCMVinclude oropharyngeal secretions, urine, cervical and vaginalexcretions, spermatic fluids, breast milk, feces and blood.

With HCMV, a large reservoir of latently infected individuals remains asignificant threat to the immuno-compromised host. The virus persistsyears after the primary infection. However, the virus is detectible onlyfor a few weeks to a few months following primary infection. Thepolymorphonuclear leukocyte is the main source of HCMV in the blood, butmonocytes and occasionally T lymphocytes may harbor HCMV in a form asyet unknown.

In general, herpes viruses such as EBV and HCMV, are characterized byseveral key properties: (1) their role as a significant pathogenresponsible for a variety of diseases; (2) the ability of the herpesvirus to remain latent in their host for life, and to be reactivated ator near the site of initial infection; and (3) to multiply efficientlyand irreversibly destroy the cells that they infect.

While it is known that antiviral agents are effective in the treatmentof viral infections, there are a number of problems associated with suchantiviral agents. As the herpes viruses are intracellular parasiteswhich use multiple biochemical pathways of the infected host cell, thereare problems associated with achieving clinically useful antiviralactivity without also adversely affecting normal host cell metabolismand causing toxicity.

As a selective inhibitor of herpes virus multiplication, acyclovirrepresents an important advance in antiviral therapy. Acyclovir wassynthesized in 1974 by Beauchamp and Schaeffer of Burroughs WellcomeCompany. Acyclovir, 9-((2-hydroxyethoxy)methyl) guanine E, demonstratedsignificant in vitro antiviral activity against herpes viruses,specifically, HSV, varicella zoster virus (VZV) and EBV.

Acyclovir is an acyclic analogue of guanosine. The inhibitory activityof acyclovir is highly selective. The enzyme thymidine kinase (TK) ofnormal uninfected cells does not effectively use acyclovir as asubstrate. However, TK encoded by the herpes simplex virus convertsacyclovir into acyclovir monophosphate, a nucleotide analogue. Themonophosphate is further converted into diphosphate by cellularguanylate kinase and into triphosphate by a number of cellular enzymes.Acyclovir triphosphate interferes with herpes simplex virus DNApolymerase and inhibits viral DNA replication. Acyclovir ispreferentially taken up and selectively converted to the activetriphosphate form by herpes virus-infected cells. Acyclovir triphosphatebinds viral DNA polymerase, acting as a DNA chain terminator. Becauseacyclovir is taken up selectively by virus-infected cells, theconcentration of acyclovir triphosphate is 40 to 100 times higher ininfected cells than in uninfected cells. Furthermore, viral DNApolymerase exhibits a 10 to 30-fold greater affinity for acyclovirtriphosphate than do cellular DNA polymerases. The higher concentrationof the active triphosphate metabolite in infected cells plus theaffinity for viral polymerases results in the very low toxicity ofacyclovir for normal host cells.

Acyclovir is available in ointment, capsule and intravenousformulations. Oral acyclovirs or other similar anti-viral drugs areindicated in the management of most cases of primary or initial genitalherpes in all patient populations and as long-term suppressive therapyin normal adults with frequently recurrent genital herpes. Oralacyclovir also is used for prophylaxis and treatment ofimmunocompromised patients with a history of clinical evidence of anactive HSV infection. Intravenous acyclovir is used in the treatment ofsevere primary or initial herpes genitalis of immunocompetent patients,some initial and recurrent mucocutaneous HSV infections inimmunocompromised patients, neonatal HSV infections and HSVE in infants,children and adults.

Although EBV and HCMV do not have virus-specific TKs, replication of theEBV and HCMV DNA is significantly impaired. Acyclovir's in vitroantiviral activity is considerably greater in HSV than HCMV.

In addition, acyclovir has an excellent safety profile and iswell-tolerated by most patients. The major adverse effect of acycloviris alteration of renal function. Adequate hydration of patients canprevent renal concretion of drug as it is eliminated by the kidneypreventing renal dysfunction.

More recently, Burroughs Wellcome has introduced Valtrex® (valacyclovirhydrochloride) the hydrochloride salt of L-valyl ester of acyclovir.Valacyclovir hydrochloride is L-valine, 2-(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy!ethylester,monochloride. Valacyclovir has the molecular formula C₁₃ H₂₀ N₆ O₄,HCl,a molecular weight of 360.80 and the following structural formula:##STR1##

Valacyclovir hydrochloride has a maximum solubility in water at 25° C.of 174 mg/ml.

After oral administration, valacyclovir is rapidly absorbed from thegastrointestinal tract. Valacyclovir is nearly completely converted toacyclovir and an L-valine by first-path intestinal and/or hepaticmetabolism. Valacyclovir is rapidly converted to acyclovir, which has invitro and in vivo inhibitory activity, against herpes simplex virusTypes 1 (HSV-1) and 2 (HSV-2) and varicella-zoster virus (VZV) . Ofthese three herpes viruses, acyclovir has highest antiviraleffectiveness against herpes simplex virus type 1. The inhibitoryactivity of acyclovir is highly selective to its affinity for the enzymethymidine kinase (TK) and encoded by HSV, VZV and Epstein-Barr virus.Thymidine kinase converts acyclovir into acyclovir monophosphate, anucleotide analog. The monophosphate is further converted intodiphosphate by cellular guanylate kinase and into triphosphates, afinite number of cellular enzymes. In vitro, acyclovir triphosphatestops replication of herpes viral DNA. This is accomplished in threeways: (1) competitive inhibition of viral DNA polymerase; (2)incorporation and termination of the growing viral DNA chain; and (3)inactivation of the viral DNA polymerase. The greater antiviral activityof acyclovir against HSV compared to VZV is due to its more efficientphosphorylation by the viral thymidine kinase (TKN). The bioavailabilityof acyclovir after administration of valacyclovir is 54.5% ±9.1% asdetermined following a one gram oral dose of valacyclovir and a 350milligram intravenous acyclovir dose.

Valacyclovir is the preferred antiviral agent due to its relatively highbioavailability. As a result of valacyclovir's increased absorption, ascompared to acyclovir for example, less frequent dosages of valacyclovirare required to reach effective antiherpetic levels.

Another antiviral agent, ganciclovir, or9-(1,3-dihydroxy-2-propoxymethyl) guanine, has increased in vitroactivity against all herpes viruses as compared to acyclovir, includingan 8 to 20 times greater activity against HCMV. While toxicity concernsprevent the use of ganciclovir for a relatively benign HCMV, in otherHCMV cases, ganciclovir has become an important antiviral treatmentoption. While the mode of action of ganciclovir against HCMV and EBV isnot entirely known, it has been suggested that these viruses may inducea kinase that efficiently promotes the obligatory initialphosphorylation of ganciclovir to its monophosphate derivative.

Another effective antiviral agent is Vistide®, or cidofovir, 1-(s)-3-hydroxy-2-(phosphonomethoxy)propyl!cytosine dihydrate with themolecular formula of C₈ H₁₄ N₃ O₆ P.2H₂ O and a molecular weight of315.22. Cidofovir again suppresses replication of the herpes virus byselective inhibition of viral DNA synthesis. Cidofovir is incorporatedinto the growing viral DNA chain which results in reductions in the rateof viral DNA synthesis.

Famvir™, famciclovir is also believed to have antiviral activity againstherpes virus 1. Famciclovir is 2-2-(2-amino-9H-purin-9-yl)ethyl!-1,3-propanediol diacetate. With amolecular formula of C₁₄ H₁₉ N₅ O₄ and a molecular weight of 321.3.Famciclovir undergoes rapid biotransformation to the active antiviralcompound penciclovir, which has inhibitory activity against herpessimplex virus types 1 and 2 and varicella zoster virus (VZV).

Famciclovir is the diacetyl 6-deoxy analog of the active antiviralcompound penciclovir. The absolute bioavailability of famciclovir is77±8%, as determined from the administration of a 500 mg famcicloviroral dose and a 400 mg penciclovir intravenous dose. In herpes simplexvirus 1 and herpes simplex virus 2, viral thymidine kinasephosphorylates penciclovir to its monophosphate form which, in turn, isconverted to penciclovir triphosphate by cellular kinases.

In addition, several additional compounds have demonstrated activityagainst the herpes viruses, antiviral agents which are currentlyundergoing clinical trial evaluation. Foscarnet sodium (trisodiumphosphonoformate) a pyrophosphate analog of phosphonoacetic acid, haspotent in vitro and in vivo activity against herpes viruses. Foscarnetinhibits the DNA polymerase of all human herpes viruses by blocking thepyrophosphate binding site which thus prevents chain elongation. Asecond newly developed antiviral agent is bromovinyl arabinosyl uracilwhich has exhibited significant inhibition of the herpes simplex virusType 1, Epstein-Barr virus and the VZV. Fluroiodoarabinosyl cytosine andits related compounds offer another potent inhibitor of herpes viruses.Like acyclovir, this antiviral agent and its activity depends onphosphorylation by herpes virus TK. However, this antiviral agent andits analogs are understood to have greater activity than acyclovir andsignificant activity against VZV and HCMV. Additionally,(S)-1-((3-hydroxy-2-phosphonyl methoxy)propyl)adenine (HPMPA) is yetanother antiviral agent which includes a new class of nucleotide analogswith in vitro activity against HSV 1 and 2, HCMV, VZV and EBV.

Valacyclovir is the preferred antiviral agent for CFS treatment wherethe etiologic agent is isolated to EBV, due to its relatively highbioavailability. As a result of valacyclovir's increased absorption, ascompared to acyclovir for example, less frequent, smaller total dosagesof valacyclovir are required to reach effective anti-herpetic levels.Similarly, for CFS treatment, where the etiologic agent is isolated toHCMV, ganciclovir is the preferred antiviral agent. As a result of itsincreased inhibition of HCMV, ganciclovir is the preferred treatmentagent.

The antiviral agent can be administered by any method appropriate,including oral, rectal, nasal, topical, vaginal and parenteral,including subcutaneous, intramuscular, intravenous, intradermal,intrathecal, and epidural. The preferred method is oral.

The amount of antiviral agent required to constitute a "therapeuticallyeffective" amount will vary based on a number of factors including theseverity of the chronic fatigue syndrome and the identity and chemicalmake-up of the patient.

In general, to provide a therapeutically effective amount of theantiviral agent, a suitable effective dose will be in the range of 0.1to 20 grams per day and preferably in the range between 0.3 and 15 gramsper day. An optimum dose is about 0.5 to 10 grams per day. The dosage,of course, varies with the body weight of the patient and so for a 70 kgindividual, a dose of 4 grams per day is optimum (e.g., 10 mg. per kg.valacyclovir every 6 hours) . In view of toxicity considerations, amaximum for a 70 kg individual is 8-12 grams per day. The desired doseis preferable presented as 2, 3, 4 or more smaller doses administered atappropriate intervals throughout the day. These smaller doses may beadministered in unit dosage forms.

In particular for valacyclovir, a patient would be administered a dosagein the range of 0.1 to 50 mg/kg body weight of the patient to 50 mg/kgof body weight of valacyclovir, hydrochloride per dosing interval,generally every six hours. The dosing interval is determined by thebioavailability of the antiviral agent and its excretion from the body.In the preferred embodiment, the patient would be administered a dosagein the range of 0.3 to 40 mg/kg of body weight of valacyclovir,hydrochloride orally every six hours. In the most preferred embodiment,a patient would be administered 10 mg/kg of body weight of valacyclovir,hydrochloride every six hours. These dosage ranges were selected toapproximate the pharmacokinetics of intravenous acyclovir, at a dosageschedule of 10 mg/kg of body weight every eight hours intravenously.

The treatment period for a CFS patient varies on a case-by-case basis.It is believed that for some, CFS is an ongoing and persistent problemrequiring continued treatment. The duration of the therapy depends onthe intensity of the CFS as affected by the therapy. One indicator of animprovement in EBV-isolated CFS patients is a decrease in the level ofIgM antibodies to the VCA for EBV. Generally, the therapy duration isproportional to the intensity of the CFS manifestation. Accordingly,following administration of an anti-viral agent, supplemental tests arehelpful to check for recurrent CFS and to determine the treatmentduration.

While valacyclovir and ganciclovir are the preferred antiviral agents,other antiviral agents which demonstrate anti-herpetic action may beused for the treatment of chronic fatigue syndrome as well. Suchantiviral agents may also be effectively administered, for example byoral methods, or as larger doses in time delay formulations. Includedamong this group of antiviral agents are acyclovir, valacyclovir,famciclovir, cidofovir, and other herpetic antiviral agents andpharmaceutically acceptable derivatives of these antiviral agents. Suchpharmaceutically acceptable derivatives include salts, hydrolyzableesters and chelates of the antiviral agents and such similar derivativeswhich have no negative pharmaceutical effect on the patient uponadministration and are thus, "pharmaceutically acceptable". Apharmaceutically acceptable salt is preferably an acidic salt derivedfrom an appropriate acid, for example, hydrochloric, sulfuric,phosphoric, maleic, fumaric, citric, tartaric, lactic, acetic orp-toluenesulphonic acid. Particularly preferred are the hydrochloridesalts.

Having generally described this invention, a further understanding canbe obtained by reference to certain specific examples which are providedherein for purposes of illustration only and are not intended to belimiting unless otherwise specified.

EXAMPLES

The present inventor has analyzed the effectiveness of various antiviralagents as a method of treatment for patients having chronic fatiguesyndrome. As a result of these patient trials, it was found thatadministration of antiviral agents, even in small doses and over a smallperiod of time, contributed to a significant improvement in the clinicalsymptoms and signs and to the normalization of the disorder.

Tests for EBV and HCMV as Etiologic Agents of CFS

Example 1. Serum antibody titers to Epstein-Barr virus (EBV) andcytomegalovirus (HCMV) were assayed in a consecutive case series of 98patients with the chronic fatigue syndrome (CFS) at a first clinic visitto a single referral center in Birmingham, Mich. from 1987-1994.Twenty-four percent of the CFS patients had evidence of a cardiomyopathydocumented by the presence of abnormal left ventricular dynamics atstress/rest (MUGA) tests. Antibodies to Epstein-Barr virus (EBV)immunofluorescent total early antigens (EAD) and cytomegalovirus (HCMV)IgM and IgG enzyme immunoassays (ELISA) were measured. The prevalence ofthese antibodies was compared to that in a non-CFS group of controlpersons from the same area. Approximately 50% of CFS and non-CFSpatients had concurrent EBV multiplication when tested by the presenceof an elevated EA antibody titer to the (EAD) diffuse complex whichneutralizes EBV encoded DNA polymerase. Elevated IgM HCMV antibodieswere uncommon (<10%) in all groups. Approximately 40% of the CFSpatients and non-CFS controls had no IgG HCMV antibody. These data areconsistent with our understanding that CFS is a persistentcardiomyopathic infection caused by EBV or HCMV, or the two herpesviruses, in combination.

In our additional research efforts, 87 patients with the chronic fatiguesyndrome (CFS) studied at a single referral center in Birmingham, Mich.exhibited a primary myocardial disease of unknown cause. These patientsexhibited abnormal oscillating T-wave flattenings and T-wave inversionsat Holter monitoring, abnormal left ventricular dynamics in stress/rest(MUGA) tests in 24.1% of 87 CFS patients undergoing this study,histopathologic evidence of a cardiomyopathy at right ventricularendomyocardial biopsy and a salutary response to ganciclovir in a s mallpreliminary subset of CFS patients with evidence of cytomegalovirus(HCMV) infection, with no concurrent multiplication of Epstein-Barrvirus. These findings are consistent with the cardiac disease that isunderstood to be the basic pathologic mechanism of the fatigue, exerciseintolerance, light-headedness, left chest ache and palpitations of CFSpatients.

Serologic Evidence. In an effort to obtain supportive serologic evidencethat the human cardiac myocyte harbors EBV, HCMV or both viruses in CFSpatients, we assayed EBV serum antibody total Early Antigen (EA) and IgMantibodies to the viral capsid antigen (VCA) and HCMV IgM and IgG serumantibodies. However, the diagnosis of another important herpes virusinfection, namely, herpes simplex virus (HSV) encephalitis was notpossible by tests of specific HSV antibodies in serum. Brain biopsy withisolation of HSV, type 1 or type 2 from affected sites was necessary fordiagnosis. It is thus believed that this is also the case for thecardiomyopathy of the CFS.

Patients. From Jan. 1, 1987 through Dec. 31, 1994, ninety-eight CFSpatients were seen in a single infectious diseases referral center inBirmingham, Mich. CFS patients met diagnostic criteria outlined by theCenters for the Disease Control and Prevention. CFS cases here are aconsecutive case series. Each CFS patient demonstrated abnormaloscillating T-wave flattenings and inversions at Holter monitoring.Twenty-four percent of the CFS patients also demonstrated abnormal leftventricular dynamics by radioisotopic gaited blood pool method.Rest/stress myocardial perfusion studies (thallium 201 or TC-99msestamibi) or, as necessary, cardiac catheterizations excluded ischemiccardiomyopathy in each case. CFS patient's demographic data were similarto other series. The mean age here was 42.3±10.6 years, and 87% werewomen. The duration of CFS was 12.2±11.3 months. Other diagnoses werehypercholesterolemia (12%), obesity (6%) and hypertensive vasculardisease (3%). No patient had diabetes mellitus.

Antibody Titers. At the initial clinical visit of each CFS patient, EBVtotal early antigens (EA) immunofluorescent antibody titers (RocheLaboratories, Columbus, Ohio) and cytomegalovirus (HCMV) IgM enzymeimmunoassays (ELISA) (Detroit Biomedical Laboratories, Detroit, Mich.)and HCMV ELISA IgG titers (Metpath Laboratories, Teteboro, N.J.) wereassayed. During the EBV infectious lytic cycle, antigen is expressedwhich can be divided into a diffuse (EA-D) complex and a cytoplasmicrestricted (EA-R) complex. We assayed the EA-D. The 52/50 KD_(a) EA-Dprotein complex neutralizes EBV encoded DNA polymerase activity. EBV EAantibody indicates recent EBV multiplication (e.g. within 90 days).Likewise, HCMV ELISA IgM enzyme immunoassays indicate recent virusmultiplication. A positive HCMV ELISA IgG titer does not differentiateconcurrent from past HCMV infection. As a control group to the CFSpatients, similar serum antibody titers were measured in 20 random wellindividuals from the same area. They were 60% women with a mean age of32 years.

RESULTS

The prevalence of EBV EA antibodies were similar in all CFS patients,both those with and those without abnormal left ventricular dynamics.The prevalence of these EBV antibodies were also the same in non-CFSwell persons. Approximately one-half of each of the groups, CFS andnon-CFS, had concurrent persistent multiplication of EBV as indicated byan EA antibody titer of ≧10. Similarly, IgG HCMV antibodies were presentin approximately 60% of each group. However, HCMV, IgM antibodies wereuncommon (>10%).

The research revealed: 1) approximately half of the CFS patients studiedhad "no evidence of EBV multiplication," when first seen and 2)approximately 40% of the CFS patients had "never been infected withHCMV". These data then are consistent with our understanding that CFS isa persistent infection with either EBV "or" HCMV or, EBV, together withHCMV in the same patient. Proof of this hypothesis requiresendomyocardial biopsies of CFS patients with tests of the cardiactissues for EBV and HCMV nucleic acids by polymerase chain reactions orin-situ hybridization.

Antiviral treatment for an appropriately selected patient is anantiviral drug such as valacyclovir for CFS patients with EBV-positivecardiac biopsies, and an antiviral agent such as ganciclovir for CFSpatients with HCMV-positive cardiac biopsies. Dual appropriateanti-viral, anti-HCMV plus anti-EBV therapy is indicated in CFS patientswith combined EBV-HCMV infections.

Example 2. EBV-Isolated CFS Patients-Test of Antiviral Treatment. TenCFS patients, in whom singular Epstein-Barr virus persistent infectionwas demonstrated, were treated and studied over a three month period.EBV active infection was documented by EBV VCA IgM antibodies and/or EBVEA elevated antibody titers. All of these patients had their energylevels reduced by 50% or more and were partially or entirelynon-functional, unable to work or maintain a household. These tenpatients had no diseases or complicating conditions which could haveaccounted for their chronic fatigue syndrome symptoms and they had noprior psychiatric diseases.

Each patient's functional status was recorded as a statisticallyvalidated energy index (EI). At each out-patient visit, subjectiveevaluation of the patient's functional status was recorded using thisenergy index. The energy index records the average subjective vitalityof the patient in the immediate 14 days prior to this specificout-patient visit. When minor illnesses such as the common coldcomplicated a visit, evaluation of the EI for a patient was delayeduntil the intercurrent problem receded.

Prior to the initiation of the antiviral treatment and followingapproximately three months of treatment, objective evaluations of theability to work and the energy index of each of the ten patients wasanalyzed. Following the treatment, each of the patients were able tofully engage in his/her activity level at work or home.

Pursuant to the energy index, a patient with a 0 EI is bedridden. Withan energy index of 1 or 2, any activity by the patient leads tooverwhelming, incapacitating fatigue. Such patients are generallylight-headed, unable to think clearly, and concentration is difficultfor any extended period of time (over 60 minutes). Left-sided chestaches, palpitations, sore throats and feverishness are frequent. Thesepatients may be out of bed for intermittent, brief periods of the day.

Patients with an energy index between 3 and 5 can, with great effort, beout of bed for several hours each day doing non-physical activities. Anyexertion significantly worsens the fatigue. These patients expressvariable light-headedness, inability to think clearly or read normally.Left-sided chest aches, palpitations, sore throats and feverishnessoccur often. Patients within this energy range cannot perform a 40 hoursedentary job or maintain the duties of a homemaker including suchactivities as cooking and cleaning. In general, CFS patients have anenergy index of 5 or less.

Patients with an energy index between 6 and 9 can assume normalactivities and maintain a 40 hour work week and, with pacing, maintain ahousehold. Such patients rarely exhibit light-headedness, foggythinking, chest aches, palpitations, feverishness and sore throats.These patients can do light physical work or exercise in moderationwithout fatigue.

Patients with an energy index of 10 have normal energy levels, staminaand a sense of well-being. Light-headedness, difficulties inconcentrating and reading ability and chest aches, palpitations, sorethroats and feverishness are absent.

This energy index and its validity were tested by the method ofconstruct validity. (Ref. Isaacs and Michael W. B. Handbook and ResearchEvaluation, page 119 Instrumentation and Measurement. Edis E. San Diego,Calif., publishers). In an effort to test the validity of the energyindex a random sample of 22 non-CFS persons was compared to 20 CFSpatients. The non-CFS persons were 17 women and 5 men with a mean age of35 years, a median age of 38 years and an overall range between 19 and62 years. The mean energy index of the non-CFS patients was 9.9, with amedian energy index of 10. The CFS patients were 17 women and 3 men witha mean age of 41, median age of 42 and an overall range in years between16 and 53. The mean energy index of the CFS group was 3.6, with a medianof 4. Under Fischer's exact test and T-tests, the gender and ages of theCFS and non-CFS groups were similar. The energy indices of the twogroups were markedly different. The power of this T-test is 1. Theeffect size of these data is 0.25. In comparison, a small effect size is0.2. A medium effect size is 0.5 and a large effect size is 0.8. Underthis scale, the energy index evaluation is a validated term, with asmall effect size.

During the initial and final clinical visits, each CFS patient wasstudied to determine the IgM antibodies to the EBV viral capsid antigen(VCA), total early antigens (EA), and enzyme immunoassays (ELISA) toHCMV IgM and HCMV ELISA IgG titers. An IgM EBV VCA antibody titerindicates infectious lytic EBV multiplication within the most recent 3month period. During the EBV infectious lytic cycle, antigen isexpressed which can be divided into a diffuse (EAD) complex and acytoplasmic restricted EAR complex (EAR). As a result, each patient'sEAD was assayed. The presence of EBV EA antibody indicates current EBVmultiplication. Likewise, an elevated cytomegalovirus or Epstein-Barrvirus IgM antibody indicates recent EBV or HCMV multiplication,respectively. The EBV VCA antibody IgM titers were done by the ELISAmethod. As a control group, similar serum antibody titers were measuredin 20 non-CFS individuals. In the non-CFS control group, the mean HCMVIgG titer was 240.

Dosage. Each of the patients was administered an oral dose ofvalacyclovir at 10 mg/kg by mouth every six hours.

Demographics. There were nine women and one man. Their ages ranged from20-67 years. Their mean age was 43.3 years. None of these ten CFSpatients had coronary artery disease as proven by either cardiaccatheterization or T_(c) 99 sestamibi cardiac stress testing. Two of theten patients had abnormal left ventricular dynamics by stress MUGAtesting. All ten patients had abnormal oscillating T-wave flattenings orT-wave inversions as detected through Holter monitoring studies.

RESULTS

EI Pre and Post Therapy. The mean EI for the 10 patients with EBV CFSwas 4.7 and the EI range was 3.5 to 5.5. At the completion of therapy,the same EBV CFS patients had a mean EI 7.5, a median EI of 7, and arange between 6-10. Prior to therapy five out of ten patients had chestpain. At the completion of the trial one out of ten patients had chestpain. At the beginning of the trial, 9 out of 10 patients hadlight-headedness, unsteadiness, inability to think well. At thecompletion of the trial, one of ten patients continued to have thesesymptoms. At the beginning of the trial, five out of ten patients hadpalpitations, while at the completion of the trial three out of tenpatients had palpitations.

Serologic Evidence. Serologic studies of the Epstein-Barr virus VCA IgMtiters were done on all patients before the beginning of the trial. Theywere positive VCA, IgM titers in five out of ten. The remainder of theEBV suspected CFS patients had elevated EBV EA antibody titers. At thecompletion of the trial, two out of ten continued to have VCA IgMpositive titers. At the beginning of the trial, seven out of ten hadpositive EA antibody titers (≧10). At the completion of the trial, eightout of ten continued to have positive EA antibody titers. Thispopulation of ten patients was characterized by little to no HCMVexperience. None had a HCMV IgM titer; eight out of ten had negative CMVIgG titers indicating no experience with this virus. One patient had atiter CMV IgG which was less than 200 and one had a titer greater than200.

While the foregoing treatments involved administration of valacycloviror ganciclovir, the test results and the results of treatment areentirely consistent with the postulate that chronic fatigue syndrome iscaused by a persistent herpes virus infection, and therefore, treatmentby other antiviral agents which demonstrate anti-herpetic antiviralactivity may be used for treatment of chronic fatigue syndrome as well.Included among this group of antiviral agents are acyclovir,ganciclovir, valacyclovir, famciclovir, cidofovir, pharmaceuticallyaccepted derivatives and mixtures thereof and other herpetic antiviralagents used in concentrations which achieve adequate antiviral levels.

Example 3. HCMV-Isolated CFS Patients-Test of Antiviral Treatment. Astudy was conducted to assess the possible efficacy of ganciclovirtreatment on a subset of CFS patients with (1) high HCMV IgG ELISAantibody titers; (2) minimal/no serologic evidence of concurrent EBVmultiplication; and (3) oscillating ECG abnormalities at Holtermonitoring.

Patients. From March, 1993, through June, 1994, 3 men and 15 women withthe mean age of 39.7 plus or minus 7.7 years, with CFS (as defined bythe USA, Centers for Diseases Control criteria), were recruited from asingle infectious diseases referral center in Birmingham, Mich.Approximately 50 patients with chronic fatigue syndrome were screenedfor inclusion in this study. The 18 CFS patients studied had a durationof overwhelming fatigue of more than 2 years and with oscillating orrepetitively abnormal aberrant T-waves at 24-hour ECG recordings usingHolter monitoring. In these 18 CFS patients, baseline standard 12 leadECG, 2-D echocardiogram, rest-stress myocardial perfusion (thallium 201or Tc-99 cardiolite) and rest-stress multiple gaited acquisitions (MUGA)studies as well as coronary angiography excluded coronary arterydisease. HCMV ELISA and HCMV ELISA IgG titers, as well as EBV capsidantigen (VCA), ELISA IgM and EBV total early antigens (EA)immunofluorescent antibody titers were assayed. Additionally, buffycoats, urine and myocardial biopsies were tested for infectious HCMV. Asa control of the occurrence of HCMV and EBV virus antibodies in normalnon-CFS persons, residing in the same area, 20 random individuals weretested for HCMV antibodies and for EBV antibodies. Holter monitoring,MUGA studies and endomyocardial biopsies in these patients were done.

Holter monitors, MUGA studies and endomyocardial biopsies were readblindly without knowledge of the patient. Also readings were repeated byat least one, and often several, other physician readers. A patient's24-hour Holter monitor was considered positive if T-waves becameintermittently inverted or flat. Labile T-wave abnormalities at Holtermonitoring were present in each CFS patient. In addition to the Holtermonitoring, at each outpatient visit, a subjective evaluation of thepatient's functional status was recorded using the energy index (EI) aspreviously described.

Infusions of Ganciclovir. After placement of a peripherally insertedcentral catheter (PICC) or a groshong catheter, ganciclovir was givenintravenously in a dose of 5 mg. per kg. at 12-hour intervals for 30days. Patients were seen once a week by the same physician and completeblood counts, SMA values and urinalysis were conducted. After 30 days,patients were seen at intervals of 4-6 weeks and evaluated at each ofthese times. They were advised to avoid exercise, fatigue and alcoholand engage in regular sleeping patterns.

Statistical Methods. Eighteen patients, 3 men and 15 women, all withCFS, with a mean age of 39.7 ranging from 29 to 51 years, wereevaluated. Statistical significance between patients meeting thecriteria for the HCMV subset and other patients with CFS were evaluatedusing tests of homogeneity of chi-square analysis and the two-tailedFisher's exact test for bivariate analysis of dichotomous data.

Results. Of the 18 patients with CFS, 13 patients improved. These 13patients are hereinafter referred to as "Group A". The gender and agesof CFS patients who improved and the 5 CFS patients that did notimprove, these 5 patients are hereinafter referred to as "Group B", weresimilar. Of the 13 CFS patients that improved, the mean age was 37;among the 5 patients that did not improve, the mean age was 41. Onepatient in each of the two groups smoked, and a single patient in GroupA had an elevated cholesterol level.

The mean duration of fatigue prior to therapy was longer, 2.8 years, inGroup B patients versus Group A patients, having a mean duration of 1.6years. Prior to receiving intravenous ganciclovir, patients in both CFSgroups experienced marked worsening fatigue with exercise. Prior totherapy, myalgia, lightheadedness and dull non-specific left-sided chestaches not related to activities were noted in both CFS groups. Otherthan the above symptoms, physical examinations in all the patients werenormal. Two patients in Group A had mitral valve prolapse and anotherpatient in Group A had an occasional mild episode of bronchial asthma.Reactive depressions were more common in Group A. Eight patients inGroup A and two patients in Group B complained of difficulty in theirability to concentrate.

Cardiac Studies. Twelve-lead ECG's were normal except for single leadT-wave inversions in standard lead III among 7 patients in Group A and 2patients in Group B.

After treatment with ganciclovir, 3 patients in Group A with previouslyabnormal myocardial dynamics reverted to normal and in 3 others, resultsof MUGA tests improved with lesser degrees of tardokinesis, hypokinesis,or left ventricular dilatation. At follow up 6 months after intravenousganciclovir treatment, one patient in Group B with an initial normalMUGA study, showed septal hypokinesis. Myocardial perfusion rest-stressstudies were normal in 13 of the 14 patients in whom the study wasconducted. Right ventricular endomyocardial biopsy showed varyingdegrees of cardiomyopathic changes characterized by myofiber disarray,myofiber dissolution, myofiber-drop out with fibrous replacement andoccasioned myofiber-hypertrophy were evident in 7 of the 14 patients.

HCMV and EBV Antibody Titers. Eight of the patients had high HCMV ELISAIgG antibody titers with a mean of 322 u. Two patients had positive IgMHCMV antibody titers. Ten of the 13 patients had little to no evidenceof EBV multiplication as tested by an elevated antibody titer to EA.

Changes in Vitality after Intravenous Ganciclovir Treatment. At thestart of ganciclovir, the severity of fatigue based on the energy index,in all patients was similar with a mean of 3 for Group A versus a meanof 2 for Group B. Six months later, the energy indices had increased.Mean indices were 7 and 4 for Groups A and B, respectively. Beforetherapy with ganciclovir, none of the patients were able to work orfunction normally. After the antiviral treatment, the 13 patients inGroup A, but none of the patients in Group B, resumed their normalpre-CFS activity levels. In general, our studies revealed that patientsin Group A had greater improvement than patients in Group B.

Toxicities in Intravenous Ganciclovir. In an initial test, a singlepatient had a transient increase in serum creatinine, but uponrecalculation of dose based upon lean body mass in a repeated test, theserum creatinine level reverted to normal. Similarly, there were noadverse events or symptoms attributable to ganciclovir.

Case Study. A 51-year-old millwright who enjoyed excellent health andwhose only risk factor for coronary artery disease was cigarette smokingsuddenly experienced overwhelming, progressive fatigue forcing him tostop work. As a result of this fatigue, he was essentially bedridden andslight exertion further worsened his fatigue. He suffered fromlightheadedness, generalized muscle aches, intermittent sore throat andan inability to think clearly. The physical exam was normal, chestx-ray, HDL cholesterol levels and urinalysis all were normal. At resting12-lead ECG showed an inverted T-wave in standard lead III, but wasotherwise normal. An ELISA IgM antibody titer to HCMV was positive,while Epstein-Barr virus antibody tests were negative. Holter monitoringshowed oscillating abnormal flat or inverted T-waves appearing with theonset of sinus tachycardias, and alternating with the reappearance ofnormal upright T-waves when tachycardias resolved.

A myocardial sestamibi perfusion rest/stress test showed reversibleischemia of the anterior, apical and inferior walls, but at cardiaccatheterization, the coronary arteries were patent. A stress MUGA studyrevealed abnormal left ventricular function with a resting ejectionfraction of 40% (normal >50%).

This patient was given daily intravenous ganciclovir treatments at 5 mg.per kg. every 12 hours, for 30 days. Five months later, the stress MUGAtest was repeated and, at this time, the resting ejection fraction hadincreased 14%, from 40% to 54%, a normal level. Five months later, thepatient's maximal cardiac ejection fraction increased from 54% to 68%.At this time, repeat myocardial perfusion studies during exercise werenormal. Left ventricular dysfunction was no longer present and thepatient's fatigue had disappeared. Subsequently, the patient resumedwork as a millwright and after a 21/2 year follow-up, remains well withnormal left ventricular function.

Conclusion. Based upon these research results, it is understood that CFSpatients with a significant ELISA IgG HCMV antibody titer, greater than120 units, with or without the presence of an IgM HCMV ELISA antibodytiter plus an absence of EBV VCA IgM antibody titer along with an EBV EAantibody titer less than 40 describes a group of CFS patients that areunderstood to derive benefit from ganciclovir treatment. Our researchshowed a significant and persistent improvement in the patient's energylevels as measured by the energy index. The use of a single thirty-daycourse of intravenous ganciclovir is arbitrary. Likewise while the abovetreatments involved ganciclovir, any of the other antiviral agentsmentioned herein may be suitable. Further supressive antiviral therapywith drugs such as an oral preparation of ganciclovir (e.g., cytovene)or oral valacyclovir for EBV CFS patients may be necessary to maintainclinical improvement.

While the best mode for carrying out the invention has been described indetail, those familiar with the art to which this invention relates willrecognize various alternative ways of performing the invention asdefined by the following claims.

What is claimed is:
 1. A method for treating chronic fatigue syndrome in a patient comprising: administering to a patient in need thereof, a therapeutically effective amount of one or more agents selected from the group consisting of grancyclovir, valcyclovir, famcyclovir, cidofovir, and pharmaceutically acceptable derivatives and mixtures thereof.
 2. The method of claim 1, wherein the patient is administered 0.1 to 20 grams of the one or more antiviral agents per day.
 3. The method of claim 1, wherein the patient is administered
 0. 3 to 15 grams of the one or more antiviral agents per day.
 4. The method of claim 1, wherein the patient is administered
 0. 5 to 10 grams of the one or more antiviral agents per day.
 5. The method of claim 1, wherein the one or more antiviral agents are administered orally.
 6. The method of claim 1, wherein the one or more antiviral agents are administered intravenously.
 7. The method of claim 1, wherein said antiviral agent is valacyclovir hydrochloride.
 8. The method of claim 7, wherein the patient is administered 0.1 to 50 milligrams of valacyclovir hydrochloride per kilogram of body weight of the patient every six hours.
 9. The method of claim 7, wherein the patient is administered 1 to 40 milligrams of valacyclovir hydrochloride per kilogram of body weight of the patient every six hours.
 10. The method of claim 7, wherein the patient is administered 10 milligrams of valacyclovir hydrochloride per kilogram of body weight of the patient every six hours.
 11. The method of claim 1, wherein said antiviral agent is ganciclovir.
 12. The method of claim 11, wherein the patient is administered 0.1 to 50 milligrams of ganciclovir per kilogram of body weight of the patient every twelve hours.
 13. The method of claim 11, wherein the patient is administered 0.3 to 40 milligrams of ganciclovir per kilogram of body weight of the patient every twelve hours.
 14. The method of claim 11, wherein the patient is administered 5 milligrams of ganciclovir per kilogram of body weight of the patient every twelve hours. 